Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblings

Area of Science:

• Immunology
• Genetics

Background:

• Recombinase-activating gene 1 (RAG1) mutations can cause severe combined immunodeficiency (SCID).
• Hypomorphic mutations may result in leaky SCID or Omenn syndrome (OS).

Observation:

• Three siblings from a consanguineous family with a homozygous hypomorphic RAG1 mutation (g.368-369delAA) were studied.
• Two siblings presented with T-B-SCID, while the youngest showed a T+B+NK+SCID phenotype with T-cell receptor (TCR) gammadelta expansion, elevated immunoglobulins, and antibody production.
• The youngest sibling developed disseminated cytomegalovirus (CMV) infection and autoimmune cytopenia.

Findings:

• The study identified distinct immunological phenotypes in siblings with the same RAG1 mutation.
• A novel T+B+NK+SCID phenotype was observed in the youngest sibling, characterized by TCR gammadelta expansion and retained antibody production.
• The patient with the novel phenotype experienced disseminated CMV infection and autoimmune cytopenia.

Implications:

• RAG1 immunodeficiency should be suspected in infants presenting with disseminated CMV infection and autoimmune cytopenia, irrespective of initial immunological findings.
• This case highlights the phenotypic variability of RAG1 mutations and the importance of genetic testing for diagnosing immunodeficiencies.
• Early diagnosis and intervention for RAG1-related disorders are critical for managing severe infections and autoimmune complications.